Use of amino acid alternating copolymer or derivative thereof in preparation of medical device, and medical device

Abstract

Disclosed in the present invention are the use of an amino acid alternating copolymer or a derivative thereof in the preparation of a medical device, and the medical device. In the use, the medical device comprises an insulating portion and a conductive portion, wherein a coating is formed on the surface of both the insulating portion and the conductive portion; and the coating is made of an amino acid alternating copolymer or a derivative thereof, the chemical structural formula of the amino acid alternating copolymer or the derivative thereof being represented by the formula below. In the use, the medical device, especially the insulating portion and the conductive portion of a neural electrode, is in direct contact with nervous tissue, and the insulating portion and the conductive portion of the medical device are both modified by means of covalent bonding to the amino acid alternating copolymer or the derivative thereof, thereby endowing the medical device (e.g., the neural electrode) with a good, long-term and stable biocompatibility, electrochemical stability, and resistance to infections, inflammations, rejection reactions and fouling.

Description

Application of amino acid alternating copolymers or their derivatives in the preparation of medical devices and the medical devices thereof Technical Field

[0001] This invention relates to the field of medical implant materials. More specifically, it relates to the application of an amino acid alternating copolymer or a derivative thereof in the preparation of a medical device and the medical device thereof. Background Technology

[0002] Today, neurological disorders are increasingly prominent, with high incidences of spinal cord injury, epilepsy, Parkinson's disease, cerebral infarction, Alzheimer's disease, sensorineural hearing loss, and anorexia nervosa, posing a significant challenge to the medical advancements in this field. In recent years, neuroscience and brain-computer interface (BCI) systems have seen continuous breakthroughs and innovations, bringing hope to the diagnosis and treatment of neurological diseases. BCI technology aims to collect and record brain electrical signals to help restore or supplement neurological disorders caused by disease or injury. Currently, prosthetic and functional stimulation technologies exist, using stimulation of the basal nerve to treat Parkinson's syndrome, tinnitus, hearing loss, paralysis, and other problems.

[0003] Neural electrodes are a crucial bridge for detecting and transmitting brain electrical activity and are the core device of brain-computer interface technology. However, the implantation of neural electrodes can lead to persistent inflammation and foreign body reactions, resulting in the formation of a thick layer of glial cells at the electrode-tissue interface. This isolates the electrode from the neuron, increases the impedance at the electrode site, and reduces the sensitivity and signal-to-noise ratio of electrochemical signals. Furthermore, as foreign bodies, electrodes are susceptible to bacterial growth, leading to nerve tissue infection and apoptosis, thus affecting communication between the electrode and the nerve. Therefore, the implantation of neural electrodes faces significant challenges in practical clinical applications.

[0004] Therefore, to obtain neural electrodes capable of stably reading and writing neuronal signals over a long period, it is necessary to construct a bidirectionally adaptable interface between the implanted neural electrode and its surface. This would improve the integration performance of the implanted electrode with the tissue interface and its signal transmission capability, reduce inflammation and rejection reactions, protein / ion adhesion and impedance caused by the implanted electrode, and enhance the biocompatibility of the neural electrode. To meet these requirements, developing neural electrodes with high biocompatibility, antibacterial properties, resistance to foreign body reactions, and without reducing the electrical performance of the electrode itself is of great significance. Summary of the Invention

[0005] Based on the above facts, the purpose of this invention is to provide the application of amino acid alternating copolymers or their derivatives in the preparation of medical devices and the medical devices thereof, so as to at least solve one of the aforementioned technical problems.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] On one hand, the present invention provides the application of an amino acid alternating copolymer or its derivative in the preparation of a medical device having low impedance, anti-inflammatory and anti-rejection properties, the medical device comprising an insulating part and a conductive part, wherein a coating is formed on the surface of both the insulating part and the conductive part;

[0008] The coating is made of an alternating amino acid copolymer or its derivatives, and the chemical structural formula of the alternating amino acid copolymer or its derivatives is shown below:

[0009] in,

[0010] R1 and R3 are each independently selected from one of the following: hydrogen, alcohol group with 1-6 carbon atoms, alkyl group with 1-9 carbon atoms, amino group with 1-6 carbon atoms, and aryl group;

[0011] R2 is selected from one of the following groups: aliphatic alkenyl, aromatic alkenyl, enol ether, and indole groups with 2-10 carbon atoms;

[0012] n is a positive integer selected from 5 to 2000.

[0013] Furthermore, R1 and R3 are each independently selected from... One of them, where * represents a connection site.

[0014] Furthermore, R2 is selected from... One of them, where * represents a connection site.

[0015] Furthermore, the amino acid alternating copolymer or its derivatives are chemically bonded to the surfaces of the insulating and conductive portions.

[0016] Furthermore, the thickness of the coating is 5nm-1000nm.

[0017] Furthermore, the medical device is an implantable medical device.

[0018] Furthermore, the medical device is made of medical implantable material.

[0019] Furthermore, the medical device is selected from neural electrodes.

[0020] Furthermore, the insulating part is made of one of the following materials: polyimide, polydimethylsiloxane, polyethylene, polypropylene, polyolefin, polylactic acid, polyxylene, and SU-8.

[0021] Furthermore, the conductive part is made of gold, platinum, nickel-titanium alloy, or graphite.

[0022] Furthermore, when the conductive part is made of platinum or graphite, the method for forming a coating on the surface of the medical device includes the following steps:

[0023] The medical device is subjected to surface activation treatment and surface coupling treatment in sequence to obtain a surface-treated medical device.

[0024] The amino acid alternating copolymer or its derivative is grafted onto the surface of the medical device.

[0025] Furthermore, when the conductive part is made of gold, the method for forming a coating on the surface of the medical device includes the following steps:

[0026] At least the insulating parts of the medical device are subjected to surface activation treatment and surface coupling treatment in sequence;

[0027] The conductive parts of the medical device are modified with thiol compounds;

[0028] The amino acid alternating copolymer or its derivative is grafted onto the surface of the medical device.

[0029] Furthermore, the method for grafting the alternating amino acid copolymer or its derivative onto the surface of the medical device includes: placing the medical device in an aqueous solution of the alternating amino acid copolymer or its derivative in water or ethanol, adjusting the pH to acidic, performing a reflux reaction in a nitrogen atmosphere, and after the reaction is completed, purifying and drying to obtain the final product.

[0030] Furthermore, the reflux reaction is carried out at a temperature of 20-95°C for a time of 0.5-8 hours.

[0031] Furthermore, when the conductive part is made of gold, the method for forming a coating on the surface of the medical device includes the following steps:

[0032] The amino acid alternating copolymer or its derivative is grafted onto the surface of the insulating portion;

[0033] The conductive portion is grafted with the alternating amino acid copolymer or its derivative.

[0034] The insulating and conductive parts are combined to form the medical device.

[0035] In another aspect, the present invention provides a medical device with low impedance, anti-inflammatory and anti-rejection properties, the medical device comprising an insulating part and a conductive part, wherein a coating is formed on the surface of both the insulating part and the conductive part;

[0036] The coating is made of an alternating amino acid copolymer or its derivatives, and the chemical structural formula of the alternating amino acid copolymer or its derivatives is shown below:

[0037] in,

[0038] R1 and R3 are each independently selected from one of the following: hydrogen, alcohol group with 1-6 carbon atoms, alkyl group with 1-9 carbon atoms, amino group with 1-6 carbon atoms, and aryl group;

[0039] R2 is selected from one of the following groups: aliphatic alkenyl, aromatic alkenyl, enol ether, and indole groups with 2-10 carbon atoms;

[0040] n is a positive integer selected from 5 to 2000.

[0041] The beneficial effects of this invention are as follows:

[0042] 1) In the applications provided in this invention, the insulating and conductive parts of the medical device, especially the nerve electrode, are in direct contact with nerve tissue. The insulating and conductive parts are simultaneously modified by covalently bonding the amino acid alternating copolymer or its derivatives to give the medical device (e.g., the nerve electrode) good and long-term stable biocompatibility.

[0043] 2) Neuroelectrodes modified with alternating amino acid copolymers or their derivatives achieved good biocompatibility without affecting their electrochemical performance. The modified neuroelectrodes exhibited reduced electrochemical impedance, and after 90 days of implantation in mice, the impedance showed no significant time-dependent change, demonstrating stable electrochemical performance. Furthermore, the average signal-to-noise ratio of the collected signals was higher than that of the unmodified electrodes.

[0044] 3) Neuroelectrodes modified with alternating amino acid copolymers exhibit anti-infection, anti-inflammatory, anti-rejection, and antifouling properties. Various types of multifunctional alternating polyamino acid derivative interface materials are constructed on the surface of neuroelectrodes for long-term stable neural interactions. Specifically, alternating peptides and their derivatives are used to construct surfaces with a cationic-π topological structure. The presence of cations (amino groups) in the structure increases the surface potential, providing high-potential surface activity and endowing the neuroe surface with anti-infection and anti-inflammatory properties. The cationic-π topological structure also endows the neuroe with antifouling properties, blood compatibility, and low immune rejection. Long-term implantation of electrodes modified with alternating amino acid copolymers significantly reduces neuronal loss in the brain, reduces the activation of astrocytes and macrophages, and weakens the inflammatory response at the neural interface, facilitating long-term and sustained collection and recording of neuronal signals.

[0045] 4) Amino acid alternating copolymers and their derivatives can not only be used for neural electrodes, but also for other implantable medical devices (such as sensors and implantable medical materials) to construct topological interfaces with cationic-π characteristics, endowing them with anti-infection, anti-inflammatory, anti-rejection and anti-fouling capabilities. Attached Figure Description

[0046] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.

[0047] Figure 1 shows the 1H NMR spectrum of the amino acid alternating copolymer or its derivative obtained in Example 1.

[0048] Figure 2 shows the 1H NMR spectrum of the amino acid alternating copolymer or its derivative obtained in Example 7.

[0049] Figure 3 shows the 1H NMR spectrum of the amino acid alternating copolymer or its derivative obtained in Example 8.

[0050] Figure 4 shows the 1H NMR spectrum of the amino acid alternating copolymer or its derivative obtained in Example 10.

[0051] Figure 5 shows the AP waves collected in the 600-6000 Hz range after implantation in the brains of mice 7, 30, and 90 days following the preparation of the neural electrode modified with an amino acid alternating copolymer or its derivatives and the unmodified neural electrode prepared in Example 3 of the present invention.

[0052] Figure 6 shows the local reaction experiment after subcutaneous implantation of the insulating substrate material modified with amino acid alternating copolymer or its derivative prepared according to the embodiments and comparative examples of the present invention. The electron microscope image shows the adhesion of the material interface to the surrounding tissue 7 days after implantation.

[0053] Figure 7 shows the local reaction experiment after subcutaneous implantation of polyimide substrate in mice.

[0054] Figure 8 shows a slice of brain tissue surrounding the neural electrodes prepared in each embodiment after removal. Detailed Implementation

[0055] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments and accompanying drawings, further explains the invention. Similar components in the drawings are indicated by the same reference numerals. Those skilled in the art should understand that the specific description below is illustrative rather than restrictive and should not be construed as limiting the scope of protection of the present invention.

[0056] To address the issues of poor biocompatibility and inflammation caused by implantable medical devices, particularly those containing both insulating and conductive components, which are prone to inflammation and rejection after implantation, this invention aims to ensure that these implantable medical devices (e.g., neural electrodes) exhibit anti-inflammatory, anti-rejection, and anti-adhesion properties against glial cells at the implantable medical device-tissue interface during long-term implantation, thereby preserving the electrochemical performance of the interface. One specific embodiment of this invention provides the application of an amino acid alternating copolymer or its derivative in the preparation of a medical device with low impedance, anti-inflammatory, and anti-rejection properties. The medical device comprises an insulating portion and a conductive portion, wherein a coating is formed on the surface of both the insulating and conductive portions.

[0057] The coating is made of an alternating amino acid copolymer or its derivatives, and the chemical structural formula of the alternating amino acid copolymer or its derivatives is shown below:

[0058] in,

[0059] R1 and R3 are each independently selected from one of the following: hydrogen, alcohol group with 1-6 carbon atoms, alkyl group with 1-9 carbon atoms, amino group with 1-6 carbon atoms, and aryl group;

[0060] R2 is selected from one of the following groups: aliphatic alkenyl, aromatic alkenyl, enol ether, and indole groups with 2-10 carbon atoms;

[0061] n is a positive integer selected from 5 to 2000.

[0062] In this embodiment, the coating has a topological structure surface with cation-π characteristics.

[0063] In this embodiment, alternating peptides and their derivatives are used to construct a surface with a cation-π topological structure in an implantable medical device. The presence of cations (amino groups) in the structure increases the surface potential, resulting in high-potential surface activity and endowing the neural electrode surface with anti-infection and anti-inflammatory properties. The cation-π topological structure also endows the neural electrode with antifouling properties, blood compatibility, and low immune rejection. Furthermore, cations and π have the ability to bind to ions and electrons, respectively, which facilitates the exchange of ion flow in tissues and electron flow in electrodes, reducing the interfacial impedance of the neural electrode.

[0064] For example, the alcohol group having 1-6 carbon atoms includes, but is not limited to, those selected from... wait.

[0065] For example, the alkyl group having 1-9 carbon atoms includes, but is not limited to, those selected from... wait.

[0066] For example, the amino group having 1-6 carbon atoms includes, but is not limited to, those selected from... wait.

[0067] For example, the aryl group includes, but is not limited to, alkylbenzenes (e.g., ), wait.

[0068] For example, the aliphatic alkenyl group having 2-10 carbon atoms includes, but is not limited to, those selected from... wait.

[0069] For example, the aromatic alkenyl group includes, but is not limited to, those selected from... wait.

[0070] For example, the enol ether group having 4-9 carbon atoms includes, but is not limited to, those selected from... wait.

[0071] For example, the indole group is selected from... wait.

[0072] In this embodiment, by simultaneously forming a coating made of the alternating amino acid copolymer or its derivatives on the surface of the conductive and insulating parts of the medical device, especially the implanted medical device (e.g., a nerve electrode), the medical device has good biocompatibility with tissues and exhibits unexpectedly low impedance, antibacterial, anti-inflammatory and anti-rejection effects during long-term implantation.

[0073] In this embodiment, the amino acid alternating copolymer or its derivatives can be obtained commercially or prepared using disclosed methods, which will not be elaborated here.

[0074] For example, in this embodiment, the preparation method of the amino acid alternating copolymer or its derivative may include the following steps:

[0075] S1. Take Add chloroform to obtain mixture M1, react at room temperature for 15-36 h, after which the reaction is completed and concentrated to obtain product S1;

[0076] S2. Take Add isopropanol solution, add trifluoromethanesulfonic acid and the product S1 at 0°C to obtain mixture M2, stir at room temperature for 15-96 h, wash and dry to obtain the amino acid alternating copolymer or its derivative.

[0077] In the above preparation method, the definitions of R1-R3 and n are as described above.

[0078] For example, in step S1, in mixture M1, The concentration is 0.01-0.1 mol / L, and the preferred molar ratio is 1:1.

[0079] For example, in step S2, in mixture M2, The concentrations of both S1 product and trifluoromethanesulfonic acid are 0.1-1 mol / L, and the preferred molar ratio is 1:1:1.

[0080] For example, in the preparation process of the amino acid alternating copolymer or its derivative, after stirring at room temperature in step S2, step S3 is further included: dissolving the polymer obtained after stirring at room temperature in step S2 with acid, heating to 25-50°C, and reacting for 3-7 hours.

[0081] For example, the acid includes, but is not limited to, one or more of the following: trifluoroacetic acid, hydrobromic acid, trifluoromethanesulfonic acid, etc.

[0082] Exemplary Including but not limited to one of the following: allylamine hydrochloride, but-3-en-1-amine, 4-vinylaniline, 2-methylpropyl-2-en-1-amine, 2-(vinyloxy)ethane-1-amine, etc.

[0083] Exemplary Including but not limited to one or more of the following: benzyl (4-oxobutyl)carbamate, isobutyraldehyde, benzaldehyde, 2-(vinyloxy)acetaldehyde, (3-oxopropyl)carbamate, etc.

[0084] For example, S describes Including but not limited to one or more of the following: potassium ornithine isocyanate, potassium lysine isocyanate, potassium glycine isocyanate, etc.

[0085] In some examples, the amino acid alternating copolymer or its derivatives are chemically bonded to the surfaces of the insulating and conductive portions. This chemical bonding ensures a tight bond between the coating and the substrate, preventing it from easily detaching and giving the electrode long-lasting and good biocompatibility.

[0086] In some examples, the coating thickness is 5 nm to 1000 nm. In more specific examples, the coating thickness includes, but is not limited to, 5 nm to 100 nm, 5 nm, 100 nm, etc. If the coating thickness is too large, such as exceeding 1000 nm, the electrode's conductivity may be affected due to the coating's barrier effect, while if the thickness is too small, the limited tissue contact area will hinder its biocompatibility. Therefore, to improve the electrode's tissue biocompatibility without affecting its conductivity, the coating thickness is preferably between 5 nm and 1000 nm.

[0087] In some examples, the insulating portion is made of one of the following materials: polyimide, polydimethylsiloxane, polyethylene, polypropylene, polyolefin, polylactic acid, polyxylene, and SU-8. In this embodiment, it has been found that the coating formed by the amino acid alternating copolymer or its derivatives can integrate well with these materials, thus fully utilizing their low impedance, antibacterial, anti-inflammatory, and anti-rejection effects.

[0088] In some examples, the conductive portion is made of gold, platinum, nickel-titanium alloy, or graphite. In this embodiment, the coating formed by the amino acid alternating copolymer or its derivatives can bond well with these conductive materials, and can more fully exert their low impedance, antibacterial, anti-inflammatory, and anti-rejection effects without affecting their inherent properties.

[0089] In this embodiment, medical devices having the insulating and conductive portions as described above are all within the scope of protection of this embodiment. Preferably, suitable medical devices are implantable medical devices, such as neural electrodes.

[0090] In some examples, this embodiment also provides a method for forming a coating on the surface of the medical device.

[0091] When the conductive part is made of platinum or graphite, the method for forming a coating on the surface of the medical device includes the following steps:

[0092] The medical device is subjected to surface activation treatment and surface coupling treatment in sequence to obtain a surface-treated medical device.

[0093] The amino acid alternating copolymer or its derivative is grafted onto the surface of the medical device.

[0094] When the conductive part is made of gold, the method for forming a coating on the surface of the medical device includes the following steps:

[0095] At least the insulating parts of the medical device are subjected to surface activation treatment and surface coupling treatment in sequence;

[0096] The conductive parts of the medical device are modified with thiol compounds;

[0097] The amino acid alternating copolymer or its derivative is grafted onto the surface of the medical device.

[0098] For example, the surface activation treatment method includes plasma treatment (e.g., oxygen plasma treatment or nitrogen plasma treatment) or Fenton treatment.

[0099] Exemplary plasma treatment conditions are: power 140-200W, pressure 20-70Pa, and time 2-6min.

[0100] An exemplary Fenton treatment method involves immersing the material in a mixed aqueous solution of ferrous sulfate and hydrogen peroxide for 1-2 hours. The preferred concentration of ferrous sulfate in the mixed solution is 0.3-0.5 mmol, and the concentration of hydrogen peroxide is 10-12 mmol.

[0101] For example, the surface coupling treatment method includes the following steps: placing the surface-treated medical device in a KH570 solution (a mixture of ethanol and water) and reacting it at 37-60°C for 10-24 hours; wherein the solvent of the KH570 solution is ethanol and water, KH570 accounts for 5-15% of the total volume of the solution, and ethanol and water account for 85-95% of the total volume of the solution (the volume ratio of ethanol to water is preferably 95:5).

[0102] For example, the thiol compound is selected from 2-propen-1-thiol.

[0103] In this embodiment, when the conductive part is made of gold, the insulating part and the conductive part can be grafted separately with the amino acid alternating copolymer or its derivative, and then the insulating part and the conductive part can be combined to form the medical device.

[0104] For example, the method of separate grafting includes:

[0105] 1) Grafting the amino acid alternating copolymer or its derivative onto the insulating portion, comprising the following steps:

[0106] The insulating portion is subjected to surface activation treatment and surface coupling treatment in sequence;

[0107] The amino acid alternating copolymer or its derivative is then grafted onto the surface of the insulating portion to obtain a surface-grafted insulating portion;

[0108] 2) Grafting the amino acid alternating copolymer or its derivative onto the conductive portion includes the following steps:

[0109] The conductive part was placed in a solution of 11-(1H-pyrrolo-1-yl)undecane-1-thiol and reacted at room temperature to obtain the modified conductive part A.

[0110] The modified conductive part A, 1,4-butyrolactone and potassium iodide magnesium were placed in a dehydrated and deoxygenated solvent and reacted at 0-35℃ for 2-10 h to obtain the modified conductive part B.

[0111] Pyridinium chlorochromate and sodium acetate were dissolved in dichloromethane to obtain a dichloromethane solution; the modified conductive part B was placed in the dichloromethane solution and reacted at 25-50℃ for 15-24h to obtain the modified conductive part C;

[0112] The modified conductive part C, the amino acid alternating copolymer or its derivatives are placed in a methanol solution and reacted at 40°C for 36-72 h. The pH of the solution is adjusted to 4.5-5.5, impurities are removed, and the mixture is dried to obtain the surface-grafted conductive part.

[0113] 3) Combine the insulating part and the conductive part.

[0114] For example, in step 2), the room temperature reaction time is 15-72 h; in the 11-(1H-pyrrolo-1-yl)undecane-1-thiol solution, the concentration of 11-(1H-pyrrolo-1-yl)undecane-1-thiol is 0.1-0.2 mol / L, preferably 0.1 mol / L.

[0115] For example, in step 2), the solvent for dehydration and deoxygenation is selected from tetrahydrofuran, toluene, and diethyl ether; the concentration of 1,4-butyrolactone in the solvent for dehydration and deoxygenation is 0.2 mol / L, and the mass concentration of potassium iodide-based magnesium is 20%.

[0116] For example, in step 2), the concentration of pyridinium chlorochromate salt in the dichloromethane solution is 0.02 mol / L, and the concentration of sodium acetate is 0.04 mol / L.

[0117] For example, in step 2), the mass concentration of the amino acid alternating copolymer or its derivative in the methanol solution is 5-20%.

[0118] For example, when the medical device is a nerve electrode, in step 3), it is assembled in the form of an insulating part, a conductive part, and an insulating part, and cured with an anisotropic conductive film (ACF) at 160-210°C for 5-10 seconds.

[0119] For example, the method of grafting the amino acid alternating copolymer or its derivative onto the surface of the medical device includes: placing the medical device in an aqueous solution of the amino acid alternating copolymer or its derivative in water or ethanol, adjusting the pH to acidic, performing a reflux reaction in a nitrogen atmosphere, and after the reaction is completed, purifying and drying to obtain the final product.

[0120] For example, the reflux reaction temperature is 20-95°C, preferably 50-95°C, and the time is 0.5-8h.

[0121] According to another specific embodiment of the present invention, a medical device with low impedance, anti-inflammatory and anti-rejection properties is provided. The medical device includes an insulating part and a conductive part, wherein a coating is formed on the surface of both the insulating part and the conductive part.

[0122] The coating is made of an alternating amino acid copolymer or its derivatives, and the chemical structural formula of the alternating amino acid copolymer or its derivatives is shown below:

[0123] in,

[0124] R1 and R3 are each independently selected from one of the following: hydrogen, alcohol group with 1-6 carbon atoms, alkyl group with 1-9 carbon atoms, amino group with 1-6 carbon atoms, and aryl group;

[0125] R2 is selected from one of the following groups: aliphatic alkenyl, aromatic alkenyl, enol ether, and indole groups with 2-10 carbon atoms;

[0126] n is a positive integer selected from 5 to 2000.

[0127] For example, the alcohol group having 1-6 carbon atoms includes, but is not limited to, those selected from... wait.

[0128] For example, the alkyl group having 1-9 carbon atoms includes, but is not limited to, those selected from... wait.

[0129] For example, the amino group having 1-6 carbon atoms includes, but is not limited to, those selected from... wait.

[0130] For example, the aryl group includes, but is not limited to, alkylbenzenes (e.g., ), wait.

[0131] For example, the aliphatic alkenyl group having 2-10 carbon atoms includes, but is not limited to, those selected from... wait.

[0132] For example, the aromatic alkenyl group includes, but is not limited to, those selected from... wait.

[0133] For example, the enol ether group having 4-9 carbon atoms includes, but is not limited to, those selected from... wait.

[0134] For example, the indole group is selected from... wait.

[0135] In the preparation of the medical device according to this embodiment, since a coating formed of the alternating amino acid copolymer or its derivative is formed on the surface of its insulating and conductive parts, it has the effects described above, which will not be repeated here.

[0136] The technical solution of the present invention will be described below with reference to some specific embodiments:

[0137] Example 1

[0138] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0139] S1. The conductive material of the nerve electrode is gold, and the insulating material layer is polyimide. The entire nerve electrode is treated with oxygen plasma. The oxygen plasma treatment conditions are: power 160W, pressure 60Pa, time 2min.

[0140] S2. The neural electrode obtained by activation in S1 is immersed in KH570 solution and reacted at 60°C for 18 hours. The solvent of KH570 solution is ethanol and water, and KH570 accounts for 15% of the total integral, while ethanol and water account for 85-95% of the total integral (volume ratio of ethanol to water is 95:5).

[0141] S3. The entire neural electrode prepared by S2 activation is immersed in an ethanol solution of 2-propen-1-thiol and reacted at room temperature for 24 hours. The concentration of 2-propen-1-thiol is 0.1 mol / L.

[0142] S4. The neural electrode prepared in S3 was placed in an ethanol-water solution containing 10% by mass of an amino acid alternating copolymer or its derivative. The pH was adjusted to 6 with sodium hydroxide. Ammonium persulfate was added dropwise under a nitrogen atmosphere and the reaction was refluxed at 80°C for 5 hours. The initiator potassium persulfate had a mass fraction of 0.5%. The volume percentage of ethanol in the ethanol-water solution was 60%. After the reaction was completed, the electrode was washed with water and ethanol and dried under vacuum to obtain a neural electrode with an amino acid alternating copolymer or its derivative grafted on its surface.

[0143] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0144] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0145] S1. Allylamine hydrochloride and isobutyraldehyde were added to chloroform at a concentration of 0.03 mol / L. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the product S1 was obtained by concentration.

[0146] S2. Potassium ornithine isocyanate was added to isopropanol, and trifluoromethanesulfonic acid and the product of S1 were added at 0℃. The mixture was stirred at room temperature for 48 hours. The concentrations of potassium ornithine isocyanate, product of S1, and trifluoromethanesulfonic acid were all 0.5 mol / L.

[0147] S3. Take 1g of the polymer obtained in S2, add 5mL of trifluoroacetic acid to dissolve it, heat to 30℃, and react for 6h. After the reaction is completed, wash and dry to obtain the amino acid alternating copolymer or its derivative, and its nuclear magnetic resonance hydrogen spectrum is shown in Figure 1.

[0148] Example 2

[0149] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0150] S1. The conductive material of the nerve electrode is gold, and the insulating material layer is polyimide. The entire nerve electrode is treated with oxygen plasma under the following conditions: power 140W, pressure 70Pa, and time 6min.

[0151] S2. Immerse the neural electrode obtained by activation in S1 into a KH570 solution and react at 37°C for 10 hours. The KH570 solution is a mixture of ethanol and water, and KH570 accounts for 10% of the total integral, while ethanol and water account for 85-95% of the total integral (the volume ratio of ethanol to water is 95:5).

[0152] S3. The entire neural electrode prepared by S2 activation is immersed in an ethanol solution of 2-propen-1-thiol and reacted at room temperature for 3 hours. The concentration of 2-propen-1-thiol is 0.1 mol / L.

[0153] S4. The neural electrode prepared in S3 was placed in an ethanol-water solution containing 3% by mass of an amino acid alternating copolymer or its derivative. The pH was adjusted to 1 with trifluoromethanesulfonic acid. Ammonium persulfate initiator was added dropwise under a nitrogen atmosphere, and the reaction was refluxed at 80°C for 5 hours. The initiator had a mass fraction of 0.1%, and the ethanol in the ethanol-water solution had a volume ratio of 80%. After the reaction was completed, the electrode was washed with water and ethanol, and then dried under vacuum to obtain a neural electrode with an amino acid alternating copolymer or its derivative grafted on its surface.

[0154] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0155] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0156] S1. Allylamine hydrochloride and (3-oxypropyl)carbamate benzyl ester were added to chloroform, with the concentrations of allylamine hydrochloride and (3-oxypropyl)carbamate benzyl ester being 0.02 mol / L. The reaction was carried out at room temperature for 36 h. After the reaction was completed, the product S1 was obtained by concentration.

[0157] S2. Potassium ornithine isocyanate was added to isopropanol, and trifluoromethanesulfonic acid and the product of S1 were added at 0°C. The mixture was stirred at room temperature for 48 hours. The concentrations of potassium ornithine isocyanate, product of S1, and trifluoromethanesulfonic acid were 0.2 mol / L. After the reaction was completed, the mixture was washed and dried to obtain the amino acid alternating copolymer or its derivative.

[0158] Example 3

[0159] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0160] S1. The conductive material of the nerve electrode is nickel-titanium alloy, and the insulating material layer is polydimethylsiloxane. The entire nerve electrode is treated with oxygen plasma under the following conditions: power 200W, pressure 20Pa, time 6min.

[0161] S2. Immerse the neural electrode obtained by activation in S1 into a KH570 solution and react at 60°C for 18 hours. The KH570 solution is a mixture of ethanol and water, and KH570 accounts for 10% of the total integral, while ethanol and water account for 85-95% of the total integral (the volume ratio of ethanol to water is 95:5).

[0162] S3. The neural electrode prepared in S2 is placed in an aqueous solution of 10% by mass of an amino acid alternating copolymer or its derivative, the pH is adjusted to 5 with trifluoromethanesulfonic acid, potassium persulfate initiator is added dropwise under a nitrogen atmosphere, and the reaction is refluxed at 80°C for 5 hours; the initiator mass fraction is 0.5%; after the reaction is completed, it is washed with water and ethanol, and dried under vacuum to obtain a neural electrode with amino acid alternating copolymer or its derivative grafted on its surface.

[0163] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0164] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0165] S1. Weigh 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol into DMSO solution and react at room temperature for 3 h. The concentrations of 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol are 0.1 mol / L and 0.05 mol / L, respectively. After the reaction is completed, dry to obtain product S1: benzyl(4-oxobutyl)carbamate.

[0166] S2. Allylamine hydrochloride is added to the product obtained in S1 and reacted in chloroform at room temperature for 24 h to obtain product S2. The concentrations of allylamine hydrochloride and benzyl (4-oxobutyl) carbamate of product S1 are 0.1 mol / L.

[0167] S3. Add trifluoromethanesulfonic acid, product S1 and product S2 to a potassium 2-isocyanate solution in isopropanol at 0℃ and stir at room temperature for 96 h. The concentrations of potassium 2-isocyanate, product S1, product S2 and trifluoromethanesulfonic acid are 0.1 mol / L.

[0168] S4. Take 1g of product S3 and add it to 5mL of trifluoroacetic acid solution. React at room temperature for 5h. After the reaction is complete, wash and dry to obtain the amino acid alternating copolymer or its derivative.

[0169] Example 4

[0170] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0171] S1. The conductive material of the nerve electrode is graphite, and the insulating material layer is polyimide. The entire nerve electrode is treated with oxygen plasma under the following conditions: power 140W, pressure 20Pa, and time 6min.

[0172] S2. The neural electrode obtained by activation in S1 is immersed in KH570 solution and reacted at 60°C for 24 hours. The solvent of KH570 solution is ethanol and water, and KH570 accounts for 10% of the total integral, while ethanol and water account for 85-95% of the total integral (volume ratio of ethanol to water is 95:5).

[0173] S3. The neural electrode prepared in S2 is placed in an aqueous solution of 15% by mass of an amino acid alternating copolymer or its derivative, the pH is adjusted to 5 with trifluoromethanesulfonic acid, potassium persulfate initiator is added dropwise under a nitrogen atmosphere, and the reaction is refluxed at 80°C for 7 hours with an initiator mass fraction of 0.5%. After the reaction is completed, the electrode is washed with water and ethanol and dried under vacuum to obtain a neural electrode with an amino acid alternating copolymer or its derivative grafted on its surface.

[0174] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0175] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0176] S1. Weigh 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol into DMSO solution and react at room temperature for 3 h; the concentrations of 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol are 0.6 mol / L and 0.3 mol / L, respectively. After the reaction is completed, dry to obtain product S1: benzyl(4-oxobutyl)carbamate.

[0177] S2. Allylamine hydrochloride was added to the product obtained in S1 and reacted in chloroform solution at room temperature for 36 h to obtain product S2. The concentrations of allylamine hydrochloride and benzyl (4-oxobutyl) carbamate of product S1 were 0.5 mol / L.

[0178] S3. Add trifluoromethanesulfonic acid, product S1 and product S2 to isopropanol containing potassium 2-isocyanate at 0℃ and stir at room temperature for 96 h to obtain product S3; wherein the concentration of potassium 2-isocyanate, product S1, product S2 and trifluoromethanesulfonic acid is 0.4 mol / L.

[0179] S4. Take 1g of product S3 and dissolve it in 5mL of hydrobromic acid. React at room temperature for 5h. After the reaction is complete, wash and dry to obtain the amino acid alternating copolymer or its derivative.

[0180] Example 5

[0181] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0182] S1. The conductive material of the nerve electrode is graphite, and the insulating material layer is polyimide. The entire nerve electrode is treated with nitrogen plasma under the following conditions: power 140W, pressure 20Pa, and time 6min.

[0183] S2. The neural electrode obtained by activation in S1 is immersed in KH570 solution and reacted at 60°C for 18 hours. The solvent of KH570 solution is ethanol and water, and KH570 accounts for 15% of the total integral, while ethanol and water account for 85-95% of the total integral (volume ratio of ethanol to water is 95:5).

[0184] S3. The neural electrode prepared in S2 was placed in an ethanol-water solution containing 15% by mass of an amino acid alternating copolymer or its derivative. The pH was adjusted to 5 with trifluoromethanesulfonic acid. Potassium persulfate, the initiator, was added dropwise under a nitrogen atmosphere. The reaction was refluxed at 80°C for 7 hours. The initiator had a mass fraction of 0.5%. The volume percentage of ethanol in the ethanol-water solution was 80%. After the reaction was completed, the electrode was washed with water and ethanol and dried under vacuum to obtain a neural electrode with an amino acid alternating copolymer or its derivative grafted on its surface.

[0185] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0186] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0187] S1. Weigh 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol into DMSO and react at room temperature for 3 h; wherein the concentrations of 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol are 0.6 mol / L and 0.3 mol / L, respectively; after the reaction is completed, dry to obtain product S1: benzyl(4-oxobutyl)carbamate.

[0188] S2. 4-Vinylaniline was added to the product of S1 and reacted in chloroform at room temperature for 15 h to obtain product S2, wherein the concentrations of allylamine hydrochloride and benzyl (4-oxobutyl) carbamate of product S1 were 0.3 mol / L.

[0189] S3. Add trifluoromethanesulfonic acid, product S1 and product S2 to isopropanol containing potassium 2-isocyanate at 0℃ and stir at room temperature for 96 h. The concentrations of potassium 2-isocyanate, product S1, product S2 and trifluoromethanesulfonic acid are 0.5 mol / L.

[0190] S4. Take 1g of product S3 and dissolve it in 15mL of hydrobromic acid. React at room temperature for 7h. After the reaction is complete, wash and dry to obtain the amino acid alternating copolymer or its derivative.

[0191] Example 6

[0192] The preparation method for neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0193] S1. The conductive material of the nerve electrode is gold, and the insulating material layer is polyimide. The entire nerve electrode is treated with nitrogen plasma under the following conditions: power 200W, pressure 20Pa, time 2min.

[0194] S2. Immerse the neural electrode obtained by activation in S1 into a KH570 solution and react at 60°C for 18 hours. The KH570 solution is a mixture of ethanol and water, and KH570 accounts for 15% of the total integral, while ethanol and water account for 85-95% of the total integral (the volume ratio of ethanol to water is 95:5).

[0195] S3. The entire neural electrode prepared by S2 activation is immersed in an ethanol solution of 2-propen-1-thiol and reacted at room temperature for 24 hours. The concentration of 2-propen-1-thiol is 0.1 mol / L.

[0196] S4. The neural electrode prepared in S3 was placed in an ethanol-water solution containing 50% by mass of an amino acid alternating copolymer or its derivative. The pH was adjusted to 5 with trifluoromethanesulfonic acid. Ammonium persulfate initiator was added dropwise under a nitrogen atmosphere, and the reaction was refluxed at 80°C for 7 hours. The initiator had a mass fraction of 0.5%, and the ethanol in the ethanol-water solution had a volume ratio of 60%. After the reaction was completed, the electrode was washed with water and ethanol, and then dried under vacuum to obtain a neural electrode with an amino acid alternating copolymer or its derivative grafted on its surface.

[0197] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0198] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0199] S1. Weigh 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol into DMSO and react at room temperature for 3 h; wherein the concentrations of 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol are 0.6 mol / L and 0.3 mol / L, respectively; after the reaction is completed, dry to obtain the S1 product benzyl (4-oxobutyl) carbamate.

[0200] S2. Add allyl-3-en-1-amine to the product obtained in S1 and react in chloroform at room temperature for 36 h to obtain product S2, wherein the concentrations of allyl-3-en-1-amine and product S1 are 0.2 mol / L.

[0201] S3. Add trifluoromethanesulfonic acid, product S1 and product S2 to isopropanol containing potassium 2-isocyanate at 0℃ and stir at room temperature for 48h. The concentrations of potassium 2-isocyanate, product S1, product S2 and trifluoromethanesulfonic acid are 1mol / L.

[0202] S4. Take 1g of product S3 and dissolve it in 10mL of hydrobromic acid. React at room temperature for 7h. After the reaction is complete, wash and dry to obtain an amino acid alternating copolymer or its derivative.

[0203] Example 7

[0204] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0205] The method for preparing the insulating material layer includes the following steps:

[0206] S1. The conductive material of the nerve electrode is gold, and the insulating material layer is polyxylene. The entire nerve electrode is treated with oxygen plasma under the following conditions: power 200W, pressure 70Pa, and time 6min.

[0207] S2. The insulating material layer obtained by activation in S1 is immersed in KH570 solution and reacted at 60°C for 10 hours. The solvent of KH570 solution is ethanol and water, and KH570 accounts for 15% of the total integral, while ethanol and water account for 85-95% of the total integral (volume ratio of ethanol to water is 95:5).

[0208] S3. The insulating material layer obtained in S2 is placed in an ethanol-water solution containing 30% by mass of an amino acid alternating copolymer or its derivative. The pH is adjusted to 4 with trifluoromethanesulfonic acid. Ammonium persulfate initiator is added dropwise under a nitrogen atmosphere, and the mixture is refluxed at 80°C for 7 hours. The initiator has a mass fraction of 0.5%, and the ethanol in the ethanol-water solution has a volume ratio of 60%. After the reaction is completed, the mixture is washed with water and ethanol, and then vacuum dried to obtain an insulating material layer with an amino acid alternating copolymer or its derivative grafted on its surface.

[0209] The method for preparing a conductor includes the following steps:

[0210] S1. Place the conductor in an aqueous solution of 11-(1H-pyrrolo-1-yl)undecane-1-thiol and react at room temperature for 15 h. The thiol concentration is 0.1 mol / L. After the reaction is complete, wash with ethanol and water and dry under vacuum.

[0211] S2. The conductor prepared in S2, 1,4-butyrolactone, and potassium iodide-based magnesium were placed in dehydrated and deoxygenated tetrahydrofuran and reacted at 35°C for 2 hours. The concentration of 1,4-butyrolactone was 0.2 mol / L, and the mass fraction of potassium iodide-based magnesium was 20%. After the reaction was completed, the mixture was washed with toluene and ethanol and then dried under vacuum.

[0212] S3. Dissolve pyridinium chlorochromate and sodium acetate in dichloromethane. Place the conductor prepared in S2 in dichloromethane and react at 50°C for 15 h. The concentration of pyridinium chlorochromate is 0.02 mol / L and the concentration of sodium acetate is 0.04 mol / L. After the reaction is complete, wash with dichloromethane and water and dry under vacuum.

[0213] S4. The conductor, amino acid alternating copolymer or its derivative obtained in S3 is placed in methanol and reacted at 20°C for 36 h, wherein the mass fraction of the amino acid alternating copolymer or its derivative is 20%, and acetic acid is added to adjust the pH of the solution to 4.5-5.5; after the reaction is completed, the mixture is washed with dichloromethane and water and then dried under vacuum.

[0214] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0215] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0216] S1. Allylamine hydrochloride and isobutyraldehyde were added to chloroform at a concentration of 0.05 mol / L. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the product S1 was obtained by concentration.

[0217] S2. Potassium ornithine isocyanate was added to isopropanol, and trifluoromethanesulfonic acid and the product of S1 were added at 0°C. The mixture was stirred at room temperature for 96 hours. The concentrations of potassium ornithine isocyanate, product of S1, and trifluoromethanesulfonic acid were 0.3 mol / L.

[0218] S3. Take 1g of the polymer obtained in S2, add 15mL of hydrobromic acid to dissolve it, heat to 50℃, and react for 3h. After the reaction is completed, wash and dry to obtain an amino acid alternating copolymer or its derivative, and its nuclear magnetic resonance hydrogen spectrum is shown in Figure 2.

[0219] The encapsulation of neural electrodes includes the following steps:

[0220] The insulating material layer and the conductor are arranged in a sandwich structure of insulating material layer / conductor / insulating material layer and cured with an anisotropic conductive film (ACF) at 160°C for 10s.

[0221] Example 8

[0222] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0223] The method for preparing the insulating material layer includes the following steps:

[0224] S1. The conductive material of the nerve electrode is gold, and the insulating material layer is SU-8. The entire nerve electrode is treated with oxygen plasma. The oxygen plasma treatment conditions are: power 200W, pressure 70Pa, time 6min.

[0225] S2. The insulating material layer obtained by activation in S1 is immersed in KH570 solution and reacted at 60°C for 24 hours. The solvent of KH570 solution is ethanol and water, and KH570 accounts for 10% of the total integral, while ethanol and water account for 85-95% of the total integral (volume ratio of ethanol to water is 95:5).

[0226] S3. The insulating material layer obtained in S2 is placed in an aqueous solution of amino acid alternating copolymer or its derivative with a mass fraction of 30%. The pH is adjusted to 4 with trifluoromethanesulfonic acid. Potassium persulfate initiator is added dropwise under a nitrogen atmosphere. The mixture is refluxed at 80°C for 7 hours. The initiator mass fraction is 0.5%. After the reaction is completed, the mixture is washed with water and ethanol and dried under vacuum to obtain an insulating material layer with amino acid alternating copolymer or its derivative grafted on its surface.

[0227] The method for preparing a conductor includes the following steps:

[0228] S1. The conductor was placed in an aqueous solution of 11-(1H-pyrrolo-1-yl)undecane-1-thiol and reacted at room temperature for 72 h. The thiol concentration was 0.1 mol / L. After the reaction was completed, the conductor was washed with ethanol and water and dried under vacuum.

[0229] S2. The conductor prepared in S2, 1,4-butyrolactone, and potassium iodide-based magnesium were placed in dehydrated and deoxygenated tetrahydrofuran and reacted at 0°C for 10 h. The concentration of 1,4-butyrolactone was 0.2 mol / L, and the concentration of potassium iodide-based magnesium was 20%. After the reaction was completed, the mixture was washed with toluene and ethanol and then dried under vacuum.

[0230] S3. Dissolve pyridinium chlorochromate and sodium acetate in dichloromethane. Place the conductor prepared in S2 in dichloromethane and react at 25°C for 24 hours. The concentration of pyridinium chlorochromate is 0.02 mol / L and the concentration of sodium acetate is 0.04 mol / L. After the reaction is complete, wash with dichloromethane and water and dry under vacuum.

[0231] S4. The conductor, amino acid alternating copolymer or its derivative obtained in S3 is placed in methanol and reacted at 20°C for 72 h; wherein the mass fraction of the amino acid alternating copolymer or its derivative is 5%, acetic acid is added to adjust the pH of the solution to 4.5-5.5, the reaction is completed, and the mixture is washed with dichloromethane and water and dried under vacuum.

[0232] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0233] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0234] S1. Weigh 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol into DMSO and react at room temperature for 3 h; wherein the concentrations of 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol are 0.6 mol / L and 0.3 mol / L, respectively; after the reaction is completed, dry to obtain product S1: benzyl(4-oxobutyl)carbamate.

[0235] S2. Allylamine hydrochloride was added to the product of S1 and reacted in chloroform at room temperature for 24 h to obtain product S2; wherein, the concentrations of allylamine hydrochloride and benzyl (4-oxobutyl) carbamate of product S1 were 0.01 mol / L.

[0236] S3. Add trifluoromethanesulfonic acid, product S1 and product S2 to an isopropanol solution of potassium 2-isocyanate at 0℃ and stir at room temperature for 96 h to obtain product S3; wherein the concentrations of potassium 2-isocyanate, product S1, product S2 and trifluoromethanesulfonic acid are 0.1 mol / L.

[0237] S4. Take 1g of product S3 and dissolve it in 15mL of trifluoroacetic acid. React at room temperature for 5h. After the reaction is complete, wash and dry to obtain an amino acid alternating copolymer or its derivative. Its 1H NMR spectrum is shown in Figure 3.

[0238] The encapsulation of neural electrodes includes the following steps:

[0239] The insulating material layer and the conductor are arranged in a sandwich structure of insulating material layer / conductor / insulating material layer and cured with anisotropic conductive film (ACF) at 210°C for 5 seconds.

[0240] Example 9

[0241] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0242] S1. The conductive material of the nerve electrode is gold, and the insulating material layer is polyimide. The insulating material layer is subjected to Fenton treatment and soaked in a mixed aqueous solution of ferrous sulfate and hydrogen peroxide for 1.5 h, wherein the concentration of ferrous sulfate is 0.45 mmol and the concentration of hydrogen peroxide is 10.5 mmol.

[0243] S2. The neural electrode obtained by activation in S1 is immersed in KH570 solution and reacted at 60°C for 24 hours. The solvent of KH570 solution is ethanol and water, and KH570 accounts for 10% of the total integral, while ethanol and water account for 85-95% of the total integral (volume ratio of ethanol to water is 95:5).

[0244] S3. The entire neural electrode prepared by S2 activation is immersed in an ethanol solution of 2-propen-1-thiol and reacted at room temperature for 24 hours. The concentration of 2-propen-1-thiol is 0.1 mol / L.

[0245] S4. The neural electrode prepared in S3 was placed in an ethanol-water solution of 15% amino acid alternating copolymer or its derivative, the pH was adjusted to 5 with trifluoromethanesulfonic acid, potassium persulfate initiator was added dropwise under a nitrogen atmosphere, and the reaction was refluxed at 80°C for 7 hours. The initiator mass fraction was 0.5%, and the volume percentage of ethanol in the ethanol-water solution was 80%. After the reaction was completed, the electrode was washed with water and ethanol, and then vacuum dried to obtain a neural electrode with amino acid alternating copolymer or its derivative grafted on its surface.

[0246] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0247] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0248] S1. Allylamine hydrochloride and benzaldehyde were added to chloroform at a concentration of 0.05 mol / L. The reaction was carried out at room temperature for 36 h. After the reaction was completed, the product S1 was obtained by concentration.

[0249] S2. Potassium ornithine isocyanate was added to isopropanol, and trifluoromethanesulfonic acid and the product of S1 were added at 0℃. The mixture was stirred at room temperature for 48 hours. The concentrations of potassium ornithine isocyanate, product of S1, and trifluoromethanesulfonic acid were 0.5 mol / L.

[0250] S3. Take 1g of the polymer obtained in S2, add 8mL of hydrobromic acid to dissolve it, heat to 40℃, react for 5h, after the reaction is completed, wash and dry to obtain an amino acid alternating copolymer or its derivative.

[0251] Example 10

[0252] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0253] S1. The conductive material of the nerve electrode is graphite, and the insulating material layer is polyimide. The entire nerve electrode is treated with oxygen plasma under the following conditions: power 200W, pressure 20Pa, time 6min.

[0254] S2. The neural electrode prepared by activation in S1 is immersed in KH570 solution and reacted at 60°C for 24 hours. KH570 accounts for 5% of the total integral, and ethanol and water account for 85-95% of the total integral (volume ratio of ethanol to water is 95:5).

[0255] S3. The neural electrode prepared in S2 is placed in an ethanol-water solution containing 30% by mass of an amino acid alternating copolymer or its derivative. The pH is adjusted to 4 with trifluoromethanesulfonic acid. Potassium persulfate, the initiator, is added dropwise under a nitrogen atmosphere. The reaction is refluxed at 80°C for 3 hours. The initiator has a mass fraction of 0.1%, and the volume percentage of ethanol in the ethanol-water solution is 60%. After the reaction is completed, the electrode is washed with water and ethanol, and then vacuum dried to obtain a neural electrode with an amino acid alternating copolymer or its derivative grafted on its surface.

[0256] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0257] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0258] S1. Allylamine hydrochloride and isobutyraldehyde were added to chloroform at a concentration of 0.06 mol / L. The reaction was carried out at room temperature for 36 h. After the reaction was completed, the product S1 was obtained by concentration.

[0259] S2. Potassium ornithine isocyanate was added to isopropanol, and trifluoromethanesulfonic acid and the product of S1 were added at 0°C. The mixture was stirred at room temperature for 96 hours. The concentrations of potassium ornithine isocyanate, product of S1, and trifluoromethanesulfonic acid were 1 mol / L.

[0260] S3. Take 1g of the polymer obtained in S2, add 5mL of trifluoromethanesulfonic acid to dissolve it, heat to 40℃, react for 5h, after the reaction is completed, wash and dry to obtain an amino acid alternating copolymer or its derivative, and its nuclear magnetic resonance hydrogen spectrum is shown in Figure 4.

[0261] Example 11

[0262] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0263] S1. The conductive material of the nerve electrode is gold, and the insulating material layer is polyimide. The entire nerve electrode is treated with oxygen plasma under the following conditions: power 200W, pressure 20Pa, time 6min.

[0264] S2. Prepare an aqueous solution of alternating amino acid copolymer or its derivative, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and N-hydroxysuccinimide in a molar ratio of 1:1:1, wherein the mass concentration of the alternating amino acid copolymer or its derivative is 10%. Immerse the entire neural electrode prepared by S1 in the solution for 24 hours, remove it, wash it, and vacuum dry it to obtain a neural electrode with the surface grafted with the alternating amino acid copolymer or its derivative.

[0265] The structure of the above-mentioned alternating amino acid copolymer or its derivative is as follows:

[0266] The preparation method of this alternating amino acid copolymer or its derivative includes the following steps:

[0267] S1. Weigh 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol into DMSO solution and react at room temperature for 3 h; wherein the concentrations of 2-iodobenzoic acid and N-benzyloxycarbonylaminobutanol are 0.6 mol / L and 0.3 mol / L, respectively; after the reaction is completed, dry to obtain the S1 product benzyl (4-oxobutyl) carbamate.

[0268] S2. Add 3-en-1-amine to the product obtained in S1 and react in chloroform at room temperature for 36 h to obtain product S2, wherein the concentrations of 3-(2-aminoethyl)indole and product S1 are 0.2 mol / L.

[0269] S3. Add trifluoromethanesulfonic acid, product S1 and product S2 to a potassium 2-isocyanate solution in isopropanol at 0℃ and stir at room temperature for 48h. The concentrations of potassium 2-isocyanate, product S1, product S2 and trifluoromethanesulfonic acid are 1mol / L.

[0270] S4. Take 1g of product S3 and dissolve it in 10mL of hydrobromic acid. React at room temperature for 7h. After the reaction is complete, wash and dry to obtain an amino acid alternating copolymer or its derivative.

[0271] Comparative Example 1

[0272] The preparation method of neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0273] S1. The conductive material of the nerve electrode is gold, and the insulating material layer is polyurethane. The entire nerve electrode is treated with oxygen plasma under the following conditions: power 200W, pressure 20Pa, time 6min.

[0274] S2. Immerse the neural electrode obtained by activation in S1 into a KH570 solution and react at 60°C for 18 hours. The KH570 solution is a mixture of ethanol and water, and KH570 accounts for 10% of the total integral, while ethanol and water account for 85-95% of the total integral (the ratio of ethanol to water is 95:5).

[0275] S3. The entire neural electrode prepared by S2 activation is immersed in an ethanol solution of 2-propen-1-thiol and reacted at room temperature for 18 hours. The concentration of 2-propen-1-thiol is 0.1 mol / L.

[0276] S4. The neural electrode prepared in S3 is placed in an aqueous solution of 10% by mass of an amino acid alternating copolymer or its derivative, the pH is adjusted to 5 with trifluoromethanesulfonic acid, potassium persulfate initiator is added dropwise under a nitrogen atmosphere, and the reaction is refluxed at 80°C for 5 hours; the initiator mass fraction is 0.5%; after the reaction is completed, it is washed with water and ethanol, and dried under vacuum to obtain a neural electrode with an amino acid alternating copolymer or its derivative grafted on its surface.

[0277] The structure of the above-mentioned amino acid alternating copolymer or its derivative is the same as that in Example 3 above.

[0278] Comparative Example 2

[0279] The preparation method for neural electrodes modified with alternating amino acid copolymers or their derivatives is as follows:

[0280] S1. The conductive material of the nerve electrode is gold, and the insulating material layer is polyimide. The entire nerve electrode is treated with nitrogen plasma. The nitrogen plasma treatment conditions are: power 200W, pressure 20Pa, time 2min.

[0281] S2. The neural electrode prepared by activation in S1 is immersed in KH570 solution and reacted at 60°C for 18 hours. The solvent of KH570 solution is ethanol and water, and KH570 accounts for 15% of the total integral, while ethanol and water account for 85-95% of the total integral (the ratio of ethanol to water is 95:5).

[0282] S3. The neural electrode prepared in S2 is placed in an ethanol-water solution containing 50% by mass of an amino acid alternating copolymer or its derivative. The pH is adjusted to 5 with trifluoromethanesulfonic acid. Ammonium persulfate initiator is added dropwise under a nitrogen atmosphere, and the reaction is refluxed at 80°C for 7 hours. The initiator has a mass fraction of 0.5%, and the volume percentage of ethanol in the ethanol-water solution is 60%. After the reaction is completed, the electrode is washed with water and ethanol, and then vacuum dried to obtain a neural electrode with an amino acid alternating copolymer or its derivative grafted only on the surface of the insulating material layer.

[0283] The structure of the above-mentioned amino acid alternating copolymer or its derivative is the same as that in Example 6.

[0284] Electrode performance testing:

[0285] Neuroelectrode implantation experiment:

[0286] The neural electrodes (i.e., modified electrodes) obtained from the above embodiments and comparative examples were selected for neural electrode implantation experiments. Unmodified electrodes and modified electrodes were implanted into the M2 region of the mouse brain, and neuronal electrical signals were collected and recorded. Simultaneously, the time-dependent changes in signal-to-noise ratio (SNR) and action potential amplitude during neuronal information transmission were studied. The SNR and action potential amplitude of the neural electrodes were recorded at 7, 30, and 90 days post-implantation.

[0287] The modified insulating material layer of the neural electrodes prepared in each embodiment was selected and implanted subcutaneously for 7 days. The tissue / protein deposition caused by foreign body reaction on the material surface was observed by scanning electron microscopy.

[0288] The electrochemical impedance variability of the neural electrodes prepared in Examples 1-11 and Comparative Examples 1-2, after implantation into the mouse brain at 7, 30, and 90 days is shown in Table 1 below. The blank control group refers to unmodified flexible gold electrodes with polyimide insulation. In Table 1, "-" indicates no detection signal. Table 1 shows that the impedance of the modified neural electrodes in the examples was reduced.

[0289] Table 1

[0290] Figure 5 shows the action potential (AP) waves collected in the 600-6000 Hz range after 7, 30, and 90 days following implantation of the neural electrodes prepared in Example 3 of the above-mentioned method into the mouse brain. The blank control group refers to the unmodified flexible gold electrode. As can be seen from Figure 5, the action potential amplitude of the modified flexible gold neural electrode is significantly increased.

[0291] The rejection resistance of the neural electrodes prepared in the above embodiments and comparative examples is shown in Figure 6. As can be seen from Figure 6, after 7 days of implantation, the adhesion of the material interface to surrounding tissues was observed using a scanning electron microscope. Compared to the blank control group, the modified neural electrodes prepared in the above embodiments and comparative examples showed reduced tissue / protein deposition on their surface due to foreign body reaction. Compared to the comparative example, the conductive and insulating portions in the embodiments were modified with alternating amino acid copolymers or their derivatives, improving the tissue adhesion performance of the conductive portion to the nerve, and resulting in a higher action potential amplitude after 3 months.

[0292] Figure 7 shows the local reaction experiments after subcutaneous implantation in mice using the above-mentioned insulating material, polyimide, in examples and comparative example 2. As can be seen from Figure 7, the swelling and inflammation of the surrounding tissue in the blank polyimide and comparative example 2 were more severe than those in the electrode insulating material modified in the examples, with a large amount of tissue adhering to the surface. Compared to comparative example 1, the modified electrode in the examples exhibited lower inflammation and rejection, and after 3 months, the action potential amplitude was also higher, showing better stability.

[0293] Long-term neuronal activity recording / stimulation experiments:

[0294] Experimental procedures and conditions:

[0295] Long-term neuronal activity recording / stimulation experiments were conducted using 6-week-old wild-type male mice (C57BL / 6, 6 weeks old). After craniotomy to remove fat and periosteum, flexible electrodes were attached to tungsten microfilaments using polyethylene glycol (PEG, mw35000). The assembled electrodes were then implanted into the M2 region of the brain using a stereotactic micromanipulator. PBS was added to dissolve the PEG, and the tungsten microfilaments were removed. Before acquiring electrophysiological signals, the in vivo impedance of all implanted electrodes was measured using an RHS128ch stimulation / recording controller (Intan, M4200) at a frequency of 1 kHz. Neuronal activity recording and stimulation were performed using a commercially available system (Intan RHX, Intan Tech). Neuronal activity data were analyzed using Matlab 2021b with a high-pass bandwidth of 300 Hz. Ninety days after implantation, the mice were deeply anesthetized, perfused with saline, and then the electrodes were removed. A portion of brain tissue was harvested, and transverse sections were stained with immunofluorescence (NeuN antibodies for neurons and F4 / 80 antibodies for macrophages).

[0296] The action potential amplitudes of the neural electrodes prepared in the above embodiments and comparative examples are shown in Table 2. The blank control group refers to unmodified flexible gold electrodes with polyimide insulation. In Table 2, "-" indicates no detection signal. As can be seen from Table 2, the action potential amplitudes acquired by the modified neural electrodes are significantly higher than those of the blank control group.

[0297] Table 2

[0298] The signal-to-noise ratio (SNR) of the neural electrodes prepared in the above embodiments and comparative examples is shown in Table 3; in Table 3, "-" indicates no detection signal. As can be seen from Table 3, compared with the blank control group (unmodified flexible gold electrode, with polyimide insulation) and the comparative example, the modified neural electrode significantly improves the signal-to-noise ratio of electrophysiological signals acquired.

[0299] Table 3

[0300] Figure 8 shows the brain tissue slices surrounding the neural electrodes prepared in the above embodiments. In Figure 8, the left image (red part) for each embodiment is the neuronal antibody NeuN, and the right image (green part) is the verification reaction antibody F4 / 80. As can be seen from Figure 8, the number of neurons near the modified neural electrodes is increased, and the number of inflammatory cells is reduced.

[0301] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all the implementation methods here. All obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. Use of an amino acid alternating copolymer or a derivative thereof for the preparation of a medical device having low impedance, anti-inflammatory, anti-rejection properties, characterized in that, The medical device comprises an insulating part and a conductive part, wherein a coating layer is formed on the surface of the insulating part and the conductive part; The material of the coating is an amino acid alternating copolymer or a derivative thereof, and the chemical structural formula of the amino acid alternating copolymer or the derivative thereof is as shown in the following formula: wherein, R1 and R3 are each independently selected from one of hydrogen, an alcohol group with 1-6 carbon atoms, an alkyl group with 1-9 carbon atoms, an amino group with 1-6 carbon atoms, and an aryl group; R2 is selected from one of an aliphatic alkenyl group with 2-10 carbon atoms, an aromatic alkenyl group, an enol ether group with 4-9 carbon atoms, and an indole group; n is a positive integer selected from 5-2000.

2. Use according to claim 1, characterized in that, each of said R1and R3is independently selected from one of the following: wherein * indicates the site of attachment; and / or said R2is selected from wherein * represents a connection site.

3. Use according to claim 1, characterized in that, The amino acid alternating copolymer or its derivative is bonded to the surface of the insulating part and the conductive part through a chemical bond.

4. Use according to claim 1, characterized in that, The thickness of the coating layer is 5-1000 nm; and / or The material of the insulating part is one of polyimide, polydimethylsiloxane, polyethylene, polypropylene, polyolefin, polylactic acid, parylene, and SU-8; and / or The material of the conductive part is gold, platinum, nickel-titanium alloy, or graphite.

5. Use according to any one of claims 1 to 4, characterized in that, The medical device is an implantable medical device, and the preferred material is a medical implant material; Preferably, the medical device is selected from a neural electrode.

6. Use according to claim 4, characterized in that, When the material of the conductive part is platinum or graphite, the method for forming a coating layer on the surface of the medical device comprises the following steps: The medical device is sequentially subjected to surface activation treatment and surface coupling treatment to obtain a surface-treated medical device; The amino acid alternating copolymer or its derivative is grafted onto the surface of the medical device.

7. Use according to claim 4, characterized in that, When the material of the conductive part is gold, the method for forming a coating layer on the surface of the medical device comprises the following steps: At least the insulating part of the medical device is sequentially subjected to surface activation treatment and surface coupling treatment; The conductive part of the medical device is modified with a thiol compound; The amino acid alternating copolymer or its derivative is grafted onto the surface of the medical device.

8. Use according to claim 6 or 7, characterized in that, The method for grafting the amino acid alternating copolymer or its derivative onto the surface of the medical device comprises the following steps: placing the medical device in an aqueous or ethanolic solution of the amino acid alternating copolymer or its derivative, adjusting the pH to be acidic, performing a reflux reaction in a nitrogen atmosphere, and purifying and drying after the reaction is completed. Preferably, the reflux reaction is performed at a temperature of 20-95°C for 0.5-8 h.

9. Use according to claim 4, characterized in that, When the material of the conductive part is gold, the method for forming a coating layer on the surface of the medical device comprises the following steps: The amino acid alternating copolymer or its derivative is grafted onto the surface of the insulating part; The amino acid alternating copolymer or its derivative is grafted onto the surface of the conductive part; The insulating part and the conductive part are combined to form the medical device.

10. A medical device having low impedance, anti-inflammatory, anti-rejection properties, comprising, The medical device comprises an insulating part and a conductive part, wherein a coating layer is formed on the surface of the insulating part and the conductive part; The material of the coating is an amino acid alternating copolymer or a derivative thereof, and the chemical structural formula of the amino acid alternating copolymer or the derivative thereof is as shown in the following formula: wherein, R1 and R3 are each independently selected from one of hydrogen, an alcohol group with 1-6 carbon atoms, an alkyl group with 1-9 carbon atoms, an amino group with 1-6 carbon atoms, and an aryl group; R2 is selected from one of an aliphatic alkenyl group with 2-10 carbon atoms, an aromatic alkenyl group, an enol ether group with 4-9 carbon atoms, and an indole group; n is selected from a positive integer from 5 to 2000. n is selected from a positive integer from 5 to

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